Major Depressive Disorder (MDD) is associated with a doubling of mortality and coronary artery disease at any age, independent of smoking or other risk factors for poor health. We have found that even premenopausal women with MDD have premature osteopenia and osteoporosis. We report here a series of highly interrelated pathophysiologically related somatic abnormalities that strongly implicate that MDD is a systemic disease. These include interrelated abnormalities in insulin, lipid, inflammatory, and autonomic-related mediators. Our data suggest that specific central nervous system (CNS) abnormalities capable of leading to the cognitive and affective manifestations of MDD also play a key role in the pathophysiology of these interconnected systemic manifestations. In some cases, the systemic manifestations persisted even in patients whose cognitive and affective manifestations were in remission. Inflammation and energy metabolism are inextricably linked by cytokine and insulin-related biology. Insulin resistance is an almost invariable accompaniment of inflammatory disease, and a proinflammatory state is the rule rather than the exception in patients with hyperinsulinemia and insulin resistance. We find abnormalities of both inflammation and insulin metabolism in patients with MDD vs. body mass index (BMI)-matched healthy control subjects. Unmedicated patients with MDD, who were in remission from depressive episodes, had significant increases in the serum levels of serum amyloid A (SAA) and C-reactive protein (CRP), two key mediators of the innate immune system. Their serum levels were significantly higher in female compared to male patients with MDD. We also found that the around-the-clock plasma levels of interleukin-6 (IL-6) were significantly higher in patients with MDD compared to BMI matched controls. In patients with MDD, the diurnal pattern of IL-6 secretion was reversed, and there was a significant loss in the complexity of its non-linear pulsatile secretory dynamics. SAA, CRP, and IL-6 are all sensitive predictive markers for subsequent coronary artery disease development, in keeping with the important role that inflammation plays in the pathogenesis of atherosclerosis. In addition to their proinflammatory state, patients with MDD who were in clinical remission had significantly reduced insulin sensitivity and increased plasma insulin, glucose, and triglyceride concentrations, when compared to BMI matched controls. These patients were young, non-obese, and had no known risk factors for the metabolic syndrome. Indices of abnormal glucose metabolism correlated with indices of inflammation. The same patients had significant increases in procoagulant compounds (e.g. factor VIII) and decreases in plasminogen-activator inhibitor-1 (PAI-1), the most potent inhibitor of fibrinolysis. In keeping with their insulin resistance and proinflammatory state, our non-obese, young patients with MDD also had significant decreases in the plasma levels of adiponectin drawn hourly for 24 consecutive hours. Adiponectin, produced only in adipose tissue, is the most potent known sensitizer of insulin receptor signalling. In patients with lipodystrophy, a condition expected to be associated with high insulin sensitivity based on the known association of obesity with insulin resistance, insulin sensitivity is impaired because of the virtual absence of adiponectin. Two CNS abnormalities, namely hypersecretion of corticotropin-releasing hormone (CRH) and norepinephrine (NE), could work together to promote the proinflammatory, insulin resistant, and hypercoagulant state seen in our patients with MDD. We and others have presented data regarding the hypersecretion of CRH in MDD. Such a state should be associated with a hypernoradrenergic state, hypothesis tested and confirmed here. We found that unmedicated patients with MDD with melancholic features had significant elevations in blood pressure, pulse rate, and in around-the-clock levels of CSF NE, plasma NE, plasma epinephrine (EPI), and plasma cortisol. CSF NE, plasma NE, and plasma cortisol levels all rose progressively during the night and peaked in the morning, the time of maximal vulnerability to myocardial infarction and sudden death. Their diurnal patterns and moment-to-moment secretion were highly concurrent, so that their collective cardiotoxic effects were evident throughout the 24 hr period. For many hrs each day, the levels of plasma NE were higher than those known to double the mortality of chronic heart failure patients, providing a mechanism for the marked increase in morbidity and mortality in patients with chronic heart failure with a superimposed depression. Our data represent the first report of increased plasma EPI in MDD. All abnormalities resolved after ECT. We replicated our findings that premenopausal women with MDD have a marked increase in the incidence of osteopenia and osteoporosis. We also found even young adults (ages 22-28) with MDD (or at high risk) have a significant increase in the incidence of osteopenia. These data were obtained in our subjects followed since early childhood by the NIMH Longitudinal Depression Study. The magnitude of bone loss correlated significantly with the amount of marital discord, assessed in each of their families at developmentally-salient time points for the past 20 yrs. In our patients with MDD, we found that bone loss occurred more often at the hip, the site most commonly involved in bone loss associated with inflammatory disease and increased IL-6 levels, rather than at the spine, the site most commonly involved in glucocorticoid-induced osteoporosis. In light of these considerations, as well as of the stimulatory action of the sympathetic nervous system on peripheral IL-6 secretion, and of the important predictive and pathophysiologic role of this cytokine in bone loss, we initiated pre-clinical studies on the effect of NE on IL-6 release by a human osteoblastic cell line (MG-63). Both NE and EPI dose-dependently stimulated IL-6 release by MG-63 cells, with a maximal 5-fold increase vs. baseline release at 100 micromolar, and without significant difference in the potency of these two adrenergic receptor agonists, consistent with an action at beta receptors, which are known to be expressed in these cells. Conversely, as expected, cortisol suppressed IL-6 secretion in a dose dependent fashion, with a 5-fold decrease at 100 nanomolar. Interestingly, the suppressive effect of cortisol was overridden by the stimulatory action of both NE and EPI. The beta-adrenergic antagonist propranolol antagonized the stimulatory effect of NE on IL-6 secretion, as well as the inhibitory effect of NE on the cortisol-induced suppression of IL-6 secretion. These results raise the hypothesis that catecholamine excess stimulates excess secretion of IL-6 by the osteoblast, providing a link between excess catecholamine and IL-6 secretion at the bone level. Over the past ten years, our group has made significant contributions to the development of an orally absorbed CRH receptor (type-1) antagonist that crosses the blood brain barrier (antalarmin). This compound has many applications, including the testing of the hypothesis that CRH excess contributes to systemic manifestations of MDD. We have found that CRH released in the periphery from sympathetic terminals has marked proinflammatory effects, and have shown that antalarmin prevents the induction of autoimmune phenomena ordinarily induced by a variety of experimental stimuli. These data suggest an important mechanism for CNS-induced inflammation in MDD and other states, and raise the question that CRH antagonists, in addition to their potential antidepressive and anxiolytic effects, may serve as a novel and effective form of anti-inflammatory intervention.